US6455573B1 - Glycosidase inhibitors and methods of synthesizing same - Google Patents

Glycosidase inhibitors and methods of synthesizing same Download PDF

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US6455573B1
US6455573B1 US09/627,434 US62743400A US6455573B1 US 6455573 B1 US6455573 B1 US 6455573B1 US 62743400 A US62743400 A US 62743400A US 6455573 B1 US6455573 B1 US 6455573B1
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group
compound
cyclic sulfate
sulfate
salacinol
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B. Mario Pinto
Blair D. Johnston
Ahmad Ghavami
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Simon Fraser University
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Simon Fraser University
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Assigned to SIMON FRASER UNIVERSITY reassignment SIMON FRASER UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GHAVAMI, AHMAD, JOHNSTON, BLAIR D., PINTO, MARIO B.
Priority to CA2396688A priority patent/CA2396688C/en
Priority to EP10185651A priority patent/EP2325179A1/de
Priority to PCT/CA2001/000010 priority patent/WO2001049674A2/en
Priority to EP01901078A priority patent/EP1248779B1/de
Priority to AU26591/01A priority patent/AU783127B2/en
Priority to AT01901078T priority patent/ATE550331T1/de
Priority to CNB018050220A priority patent/CN100341870C/zh
Priority to JP2001550214A priority patent/JP5053494B2/ja
Priority to US10/226,657 priority patent/US20030191104A1/en
Publication of US6455573B1 publication Critical patent/US6455573B1/en
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Priority to US10/877,490 priority patent/US20050065139A1/en
Assigned to MEDINNOVA PARTNERS INC. reassignment MEDINNOVA PARTNERS INC. SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MIMOS THERAPEUTICS INC.
Priority to US11/368,014 priority patent/US8389565B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D345/00—Heterocyclic compounds containing rings having selenium or tellurium atoms as the only ring hetero atoms

Definitions

  • This application relates to methods for synthesizing Salacinol, its stereoisomers, and analogues thereof potentially useful as glycosidase inhibitors.
  • NIDD non-insulin dependent diabetes
  • glucosidase inhibitors have been isolated from Salacia reticulate, a plant native to submontane forests in Sri Lanka and parts of India (known as “Kotala himbutu” in Singhalese).
  • Salacia reticulata is a woody climbing plant which has been used in the Ayurvedic system of Indian medicine in the treatment of diabetes.
  • Ayurvedic medicine advised that a person suffering from diabetes should drink water left overnight in a mug carved from Kotala himbutu wood.
  • Yoshikawa et al. reported the isolation of the compound Salacinol from a water-soluble fraction derived from the dried roots and stems of Salacia reticulate. 1 Yoshikawa et al. determined the structure of Salacinol, shown below, and demonstrated its efficacy as an ⁇ -glucosidase inhibitor.
  • Kotalanol contains a thiosugar sulfonium ion and an internal sulfate providing the counterion:
  • Salacinol and Kotalanol may potentially have fewer long-term side effects than other existing oral antidiabetic agents.
  • oral administration of acarbose in the treatment of Type II diabetes results in undesirable gastrointestinal side effects in some patients, most notably increased flatulence, diarrhoea and abdominal pain.
  • Salacinol has been used as a therapy for diabetes in the Ayurvedic system of traditional medicine for many years with no notable side effects reported.
  • recent animal studies have shown that the oral ingestion of an extractive from a Salacia reticulate trunk at a dose of 5,000 mg/kg had no serious acute toxicity or mutagenicity in rats. 3
  • the Salacia reticulate plant is, however, in relatively small supply and is not readily available outside of Sri Lanka and India. Accordingly, it would be desirable if Salicinol, Kotalanol and analogues thereof could be produced synthetically.
  • Carbohydrate processing inhibitors have also been shown to be effective in the treatment of some non-diabetic disorders, such as cancer. While normal cells display characteristic oligosaccharide structures, tumor cells display very complex structures that are usually found in embryonic tissues. It is believed that these complex structures provide signal stimuli for rapid proliferation and metastasis of tumor cells.
  • a possible strategy for therapeutic use of glucosidase inhibitors is to take advantage of the differential rates of normal vs cancer cell growth to inhibit assembly of complex oligosaccharide structures.
  • the indolizidine alkaloid swainsonine an inhibitor of Golgi ⁇ -mannosidase II reportedly reduces tumor cell metastasis, enhances cellular immune responses, and reduces tumor cell growth in mice. 4 Swainsonine treatment has led to significant reduction of tumor mass in human patients with advanced malignancies, and is a promising drug therapy for patients suffering from breast, liver, lung and other malignancies.
  • the compounds of the present invention may also find application in the treatment of Alzheimer's disease due to their stable, internal salt structure.
  • Alzheimer's is characterized by plaque formation in the brain caused by aggregation of a peptide, ⁇ -amyloid, into fibrils. This is toxic to neuronal cells.
  • X is selected from the group consisting of S, Se, and NH.
  • Such compounds include stereoisomers of Salicinol.
  • the target compounds have a stable, internal salt structure comprising heteroatom cation X and a sulfate anion; the substituents may vary without departing from the invention.
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides; and R 6 is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals, such as alkyl, alkenyl, alkynyl, aryl, and alkoxy substituents containing any suitable functionality.
  • Processes for the production of compounds of the general formula (I) comprising reacting a cyclic sulfate having the general formula (II) with a 5-membered ring sugar having the general formula
  • X is selected from the group consisting of S, Se, and NH
  • R 1 and R 2 are selected from the group consisting of H and a protecting group
  • R 3 is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals and their protected derivatives
  • R 4 , R 5 and R 6 are the same or different and are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides and their protected derivatives.
  • the cyclic sulfate is a 2,4-di-O-protected-D-or L-erythritol-1,3-cyclic sulfate, such as 2,4-O-Benzylidene-D-or L-erythritol-1,3-cyclic sulfate (i.e. R 1 and R 2 comprise a benzylidene protecting group); R 3 is H or a protected polyhydroxylated alkyl chain; and R 4 , R 5 and R 6 are selected from the group consisting of OH and a protected OH group, such as OCH 2 C 6 H 5 .
  • the synthetic processes comprise the step of opening the cyclic sulfate (II) by nucleophilic attack of the heteroatom X on the sugar (III).
  • the cyclic sulfate (II) may be reacted with a 6-membered ring sugar having the general formula (XI) to yield a compound having the general formula (XII):
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides and R 7 is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals.
  • R 1 , R 2 and R 3 are as described above in respect of compound (II) and R 4 , R 5 , R 6 and R 7 are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides and their protected derivatives.
  • the application also relates to pharmaceutical compositions comprising an effective amount of a compound according to formula (I) or (XII) together with a pharmaceutically acceptable carrier and to methods of treating carbohydrate metabolic disorders, such as non-insulin dependent diabetes, or different forms of cancer or Alzheimer's disease by administering to a subject in need of such treatment an effective amount of such compounds.
  • Salacinol is a naturally occurring compound which may be extracted from the roots and stems of Salacia reticulata, a plant native to Sri Lanka and India. This application relates to synthetic routes for preparing Salacinol (1), and its nitrogen (2) and selenium (3) analogues shown below.
  • This application also relates to synthetic routes for preparing the stereoisomers of compounds (1) to (3).
  • Such analogues and stereoisomers (including stereoisomers of Salacinol) comprise a new class of compounds which are not naturally occurring and may find use as glycosidase inhibitors.
  • Scheme 1(a) shows the general synthetic scheme developed by the inventors for arriving at the target compounds.
  • the inventors followed a disconnection approach for determining the preferred synthetic route.
  • a reasonable disconnection is one that gives the 5-membered-ring sugars (D) since they can be synthesized easily from readily available carbohydrate precursors.
  • Nucleophilic substitution at C 1 of the sulfate fragment (E) can then yield the target molecules (Scheme 1(a)).
  • a potential problem with this approach is that the leaving group (L) might act later as a base to abstract the acidic hydrogens of the sulfonium salt 7 and produce unwanted products. Therefore, the cyclic sulfate (F) may be used instead of (E) to obviate the problems associated with leaving group (L).
  • Compound (G) may similarly be used as a cyclic sulfate reagent and is a protected version of (F).
  • Scheme 1(b) below shows generally the coupling reactions for producing the target compounds (A)-(C).
  • Route 1 of Scheme 1(b) shows the general strategy of reacting a cyclic sulfate with a 5-membered ring sugar to produce an intermediate compound, which may include benzyl or other protecting groups. As described in further detail below, the intermediate compound is then deprotected to yield the target compounds. The inventor s have determined that Route 2 of Scheme 1(b), a possible side reaction, does not occur.
  • Cyclic sulfates and 5-membered-ring sugars were prepared in accordance with the synthetic schemes described below. As will be apparent to a person skilled in the art, other equivalent schemes for producing the reagents of the invention could be substituted.
  • Cyclic sulfates were prepared in analogous fashion to the ethylidene acetal. 8
  • the cyclic sulfate (7) was synthesized in 4 steps starting from D-glucose (Scheme 2).
  • 2,4-O-Benzylidene-D-erythrithol (5) was synthesized from D-glucose in two steps, 9,10 and then treated with thionyl chloride to yield the cyclic sulfite (6) which was oxidized to the cyclic sulfate (7) as described by Calvo-Flores et al. 8
  • the enantiomer (10) was also synthesized using the same route but starting from L-glucose (Scheme 3).
  • 1,4-anhydro-3-O-benzyl-4-thio-D-arabinitol (11), was synthesized in 9 steps starting from D-glucose (Scheme 4).
  • 11 Benzylation of the compound (11), using benzyl bromide in DMF yielded 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D-arabinitol (12) in 90% yield.
  • Compound (11) was debenzylated to give 1,4-anhydro-4-thio-D-arabinitol (13) in 97% yield using a Birch reduction.
  • 1,4-Di-O-methanesulfonyl-2,3,5-tri-O-benzyl-D-xylitol (15) is also a key intermediate for the synthesis of the aza and selena sugars (16) and (17).
  • 1,4-Dideoxy-1,4-imino-L-arabinitol (16) 13 was synthesized in 7 steps starting from D-xylose (Scheme 5).
  • the enantiomer (19) 13 was synthesized in an analogous way starting from L-xylose (Scheme 6).
  • Compound (19) was also synthesized in 10 steps starting from D-xylose.
  • the target compounds (1)-(3) were prepared by opening of the cyclic sulfates by nucleophilic attack of the heteroatoms on the 5-membered rings (Scheme 1(b) above).
  • the heteroatom gives rise to a positively charged cation and the cyclic sulfate gives rise to a negatively charged counterion.
  • This internal salt structure may explain the stability of the target compounds toward decomposition by further nucleophilic attack.
  • Salacinol (1) was synthesized by nucleophilic substitution of the protected thio-arabinitol (12) with the cyclic sulfate (10) (1.2 equiv) in dry acetone containing K 2 CO 3 , to give the protected intermediate compound (21) in 33% yield. Hydrogenolysis of the benzyl and benzylidene groups in AcOH:H 2 O, 4:1 afforded Salacinol (1) in 67% yield (Scheme 7).
  • the isomers were separable by analytical HPLC.
  • the inventors have assigned the name “Blintol” to the new selenium analogue (3).
  • the isomers were separable by analytical HPLC.
  • Compound (29) is a diastereomer of Blintol (3).
  • the nitrogen analogue intermediate (30) was made by the reaction of the deprotected imino-arabinitol (19) with the cyclic sulfate (10) in a good yield 72% (Scheme 13).
  • Compound (19) was not soluble in acetone so the reaction was performed in dry methanol.
  • the inventors have assigned the name “Ghavamiol” to the new nitrogen analogue (2).
  • Compound (30) was deprotected to give Ghavamiol (2) in 64% yield.
  • the enantiomer intermediate (31) was made by the reaction of the deprotected imino-arabinitol (16) with the cyclic sulfate (7) in a good yield 72% (Scheme 14). A side product (21%) which was identified to be the product of methanolysis of the cyclic sulfate was obtained. Compound (31) was deprotected to give compound (32) in 77% yield. Compound (32) is the enantiomer of Ghavamiol (2).
  • target compounds having potential application as glycosidase inhibitors may be synthesized in the manner described above using 6-membered rather than 5-membered ring heterocycles as reagents.
  • the general formulas for the 6-membered sugar reagent and resulting target compound are as shown below.
  • the 6-membered ring target compound shares the same internal salt structure as the 5-membered ring embodiment.
  • the substituent groups may vary as described above without departing from the invention.
  • the cyclic sulfite (6) (3.5 g, 14 mmol) was dissolved in a mixture of MeCN (50 mL) and CCl 4 (50 mL), and NaIO 4 (4.1 g, 1.5 equiv) and RuCl 3 .H 2 O (50 mg) were added followed by H 2 O (50 mL). The mixture was stirred vigorously at rt until TLC (hex:EtOAc,4:1) showed complete disappearance of the starting material. The mixture was diluted with Et 2 O (200 mL) and washed with H 2 O (200 mL) and brine (200 mL). The organic solution was dried (Na 2 SO 4 ) and concentrated on a rotary evaporator.
  • the product was purified by flash chromatography [hex:EtOAc, 4:1+0.1% Et 3 N] to yield a white solid (3.5 g, 95%). A portion of the product was recrystallized from EtOAc:hex. Mp 115-125° C.
  • the product was partitioned between CH 2 Cl 2 (150 mL) and water (50 mL), and the organic solution was washed with water (50 mL) and brine (50 mL) and dried (MgSO 4 ).
  • the product was purified by flash chromatography (hex:EtOAc, 3:1) to give a yellow oil (4.74 g, 80%).
  • the protected compound was dissolved in AcOH:H 2 O, 4:1 (3 mL) and stirred with Pd—C (80 mg) under H 2 (52 psi). After 60 h the reaction mixture was filtered through a pad of Celite, which was consequently washed with MeOH. The combined filtrates were concentrated and the residue was purified by column chromatography.

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US09/627,434 2000-01-07 2000-07-28 Glycosidase inhibitors and methods of synthesizing same Expired - Lifetime US6455573B1 (en)

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Application Number Priority Date Filing Date Title
US09/627,434 US6455573B1 (en) 2000-01-07 2000-07-28 Glycosidase inhibitors and methods of synthesizing same
AT01901078T ATE550331T1 (de) 2000-01-07 2001-01-05 Glycosidasehemmer und verfahren zu dessen herstellung
JP2001550214A JP5053494B2 (ja) 2000-01-07 2001-01-05 サラシノール類似化合物、ならびにサラシノールおよびサラシノール類似化合物の合成方法
PCT/CA2001/000010 WO2001049674A2 (en) 2000-01-07 2001-01-05 Glycosidase inhibitors and preparation thereof
EP01901078A EP1248779B1 (de) 2000-01-07 2001-01-05 Glycosidasehemmer und verfahren zu dessen herstellung
AU26591/01A AU783127B2 (en) 2000-01-07 2001-01-05 Glycosidase inhibitors and preparation thereof
CA2396688A CA2396688C (en) 2000-01-07 2001-01-05 Glycosidase inhibitors and methods of synthesizing same
CNB018050220A CN100341870C (zh) 2000-01-07 2001-01-05 葡糖苷酶抑制剂及其合成方法
EP10185651A EP2325179A1 (de) 2000-01-07 2001-01-05 Glycosidasehemmer und Verfahren zu dessen Herstellung
US10/226,657 US20030191104A1 (en) 2000-01-07 2002-08-22 Glycosidase inhibitors and methods of synthesizing same
US10/877,490 US20050065139A1 (en) 2000-07-28 2004-06-25 Glycosidase inhibitors and methods of synthesizing same
US11/368,014 US8389565B2 (en) 2000-01-07 2006-03-02 Glycosidase inhibitors and methods of synthesizing same

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US20050065139A1 (en) * 2000-07-28 2005-03-24 Pinto Brian Mario Glycosidase inhibitors and methods of synthesizing same
US20060193845A1 (en) * 2004-09-14 2006-08-31 Elixir Pharmaceuticals, Inc. Combination therapy for controlled carbohydrate digestion
US20060247222A1 (en) * 2000-01-07 2006-11-02 Simon Fraser University Glycosidase inhibitors and methods of synthesizing same
US20070135486A1 (en) * 2003-06-12 2007-06-14 Osamu Muraoka Cyclic onium compounds and glucosidase inhibitors
US20080279808A1 (en) * 2005-11-15 2008-11-13 Jorge Ruas Da Silva 2,3,4,5-Tetrahydroxy-6-Sulfooxy Hexanoic Acid, Pharmaceutically Acceptable Salts and Equilibrium Forms Thereof, Processes for Their Preparation, Pharmaceutical Compositions Comprising Such Compounds and Their Medical Use
US20090011060A1 (en) * 2007-07-06 2009-01-08 Peter Koepke Campsiandra angustifolia extract and methods of extracting and using such extract
US20090017140A1 (en) * 2007-07-09 2009-01-15 Peter Koepke Maytenus abenfolia extract and methods of extracting and using such extract
US20090035395A1 (en) * 2007-08-01 2009-02-05 Peter Koepke Spondias mombin l. extract and methods of extracting and using such extract
US20090074891A1 (en) * 2007-09-18 2009-03-19 Peter Koepke Combretum laurifolium mart. extract and methods of extracting and using such extract
WO2013133685A1 (en) 2012-03-09 2013-09-12 Biotropics Malaysia Berhad Extract formulations of rhodamnia cinerea and uses thereof
US9481700B2 (en) 2007-05-22 2016-11-01 Amicus Therapeutics, Inc. Method for preparing isofagomine and its derivatives
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof

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JP4516282B2 (ja) * 2003-04-24 2010-08-04 森下仁丹株式会社 新規なα−グルコシダーゼ阻害活性を有する物質およびこれを含有する食品
EP2422813A4 (de) * 2009-04-22 2014-07-23 Fujifilm Corp Mittel zur steuerung des zusammensetzungsverhältnisses der darmbakterienflora
JP5934120B2 (ja) 2011-01-31 2016-06-15 学校法人近畿大学 環状スルホニウム塩、その製造方法およびそれを用いたα−グルコシダーゼ阻害剤
JP5635932B2 (ja) * 2011-03-30 2014-12-03 富士フイルム株式会社 プロセシンググルコシダーゼ阻害剤
JP6268014B2 (ja) 2014-03-20 2018-01-24 富士フイルム株式会社 サラシノールの製造に有用な化合物およびそれらの製造法、サラシノールの製造法、ジオール基の保護方法および脱保護方法、並びにジオール基の保護剤

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US20050065139A1 (en) * 2000-07-28 2005-03-24 Pinto Brian Mario Glycosidase inhibitors and methods of synthesizing same
US7534811B2 (en) 2003-06-12 2009-05-19 Kinki University Cyclic onium compounds and glucosidase inhibitors
US20070135486A1 (en) * 2003-06-12 2007-06-14 Osamu Muraoka Cyclic onium compounds and glucosidase inhibitors
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US20080279808A1 (en) * 2005-11-15 2008-11-13 Jorge Ruas Da Silva 2,3,4,5-Tetrahydroxy-6-Sulfooxy Hexanoic Acid, Pharmaceutically Acceptable Salts and Equilibrium Forms Thereof, Processes for Their Preparation, Pharmaceutical Compositions Comprising Such Compounds and Their Medical Use
US8017650B2 (en) 2005-11-15 2011-09-13 Jorge Ruas Da Silva 2,3,4,5-tetrahydroxy-6-sulfooxy hexanoic acid, pharmaceutically acceptable salts and equilibrium forms thereof, processes for their preparation, pharmaceutical compositions comprising such compounds and their medical use
US9481700B2 (en) 2007-05-22 2016-11-01 Amicus Therapeutics, Inc. Method for preparing isofagomine and its derivatives
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EP1248779B1 (de) 2012-03-21
AU783127B2 (en) 2005-09-29
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US20030191104A1 (en) 2003-10-09
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ATE550331T1 (de) 2012-04-15
WO2001049674A2 (en) 2001-07-12
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JP5053494B2 (ja) 2012-10-17
EP2325179A1 (de) 2011-05-25

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